Oral delivery of active pharmaceutical ingredients (in the following abbreviated as API) is an important research field in pharmaceutical technology. On the way to the site of therapeutic activity for local-acting APIs as well as to the site of drug absorption for systemically exposed compounds, the bioavailability of APIs is compromised by several barriers. It starts with the luminal instability of a number of APIs in the harsh conditions of the gastro-intestinal tract, particularly in the stomach. Thus, a delivery system has to cope with acidic and enzymatic barrier to bring APIs intact to the site of absorption or of local action. Another substantial hurdle is the permeation step through the gut wall. In particular, large molecules are too bulky to be passively absorbed through the intestinal wall. Other ways of absorbing would have to be used such as paracellular transport, transcytosis or uptake by the intestinal M-cells. Some APIs have therapeutic action locally in the gastrointestinal lumen, in the mucosa, either binding to specific cell receptors or to cytokines produced by the epithelial cells. In these cases, the hurdles related to the systemic exposure through the gastrointestinal mucosa are of benefit for locally acting large molecules. In both events, i.e. systemically exposure or locally acting APIs, a common challenge is their delivery to the site of action without compromising their biological activity.
Among various options for protecting and delivering APIs to their site of action within the gastrointestinal tract after oral administration, a lipid-based drug delivery can be envisaged. However, a standard lipid based system is not able to target a specific region of the gut. Furthermore, one of the technical challenges is that an aqueous environment would be required for many APIs. A hydrophilic micro-environment might be obtained by inverse microemulsion or liposomes. A basic issue of using liposomes or W/O microemulsions is that upon dilution in the gastrointestinal tract, there are phase changes taking place leading to colloidal instability. Moreover, these lipid-based formulations are digested by the lipophilic enzymes including the phospholipase A2, which degrades liposomes and other phospholipid-based systems. Therefore, a more stable hydrophilic compartment would be desirable for drug inclusion.
One option for including an API in a hydrophilic compartment is microencapsulation. Many different techniques for the production of microspheres and microcapsules have been described. An overview over these techniques is provided by M. Whelehan, et al., in Journal of Microencapsulation, 2011; 28(8): 669-688. The vibrating nozzle technique is a widely used method for the production of microspheres and microcapsules. This technique is for example disclosed in WO 2009/130225 and by M. Homar, et al., in Journal of Microencapsulation, February 2007; 24(1): 72-81, C.-Y. Yu, et al., in Journal of Microencapsulation, 2010; 27(2): 171-177, H. Brandenberger, et al., in Journal of Biotechnology 63 (1998) 73-80 and G. Auriemma, et al., in Carbohydrate Polymers 92 (2013) 367-373.
Microspheres and microcapsules obtained by the known methods contain the API encapsulated within a gel. Such gels can be stable even under the harsh chemical conditions for example in the stomach and therefore can protect the API for a certain period of time until the gel is degraded and the API is released. However, degradation of the gel can be fast and it can be difficult to tailor the release of the API in a desired manner. Furthermore, gels often provide only little protection against enzymatic digestion.
As another drug delivery system the use of nanotubes has been proposed (Price R. R., et al., J. Microencapsulation 2001; 18(6): 713-22). Nanotubes showed the capacity of storing APIs in their lumen or to adsorb compounds on their surface. Both luminal and surface additions and modifications have been proposed to increase the loading efficiency of the tubes or to modify the release properties of this system.
Many of these modifications were reviewed by Liu M., et al., Prog. Polym. Sci. 2014; 39(8): 1498-525. However, the release of API from nanotubes is generally fast and nanotubes loaded with APIs also do not provide adequate protection of the API for example against enzymatic digestion.
Therefore, there is still a need for further improved drug delivery systems which overcome the above problems. In particular, there is a need for drug delivery systems which effectively protect the API against enzymatic digestion, in particular against enzymatic digestion along the gastrointestinal tract, which can be easily prepared with standard techniques and which allow tailoring the release profile of the API from a pharmaceutical preparation containing the drug delivery system after administration.